Containers for parenteral fluids

ABSTRACT

A flexible transparent container for improved storage of oxygen sensitive parenterally administerable agents comprising an inner, primary container enclosed in a substantially oxygen impermeable outer envelope with an oxygen absorber, capable of consuming essentially all residual oxygen after the outer envelope is sealed, and for sufficient period also the oxygen penetrating said envelope. The inner container is made of a polypropylene containing flexible polymeric material compatible with lipophilic agents capable of forming both permanent and peelable seals, while the envelope is made of a substantially water impermeable flexible multilayered polymeric material comprising a first outer substantially water impermeable polymeric film with oxygen barrier forming capacity, assembled with a second, inner polymeric film with a supplementary oxygen barrier forming capacity. The container essentially maintains its characteristics after being subjected to sterilization by steam or radiation.

This application is a divisional application of U.S. Application Ser.No. 08/905,547, filed Aug. 4, 1997, now U.S. Pat. No. 6,007,529, U.S.Provisional 60/023,194, filed Aug. 5, 1997, which in turn claimspriority from Swedish Patent Application No. 9601348-7, filed Apr. 10,1996, all of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to flexible polymeric containers with animproved long term storage capacity of such sensitive medical fluidsthat are intended to be administered parenterally. The containers haveability to withstand several types of final sterilization after beingfilled with medical fluids and seals, substantially without losing itsbarrier capacity or any other important characteristics. It comprises anouter sealed airtight envelope and an inner container filled with one orseveral medical agents which has high compatibility also to storedlipophilic agents.

BACKGROUND OF THE INVENTION

Traditionally, fluids aimed for parenteral administration to the bloodstream of patients have been packaged in glass containers. There has,however, been much industrial efforts devoted to find alternativepolymeric materials which are less resource consuming, cheaper and moreconvenient to handle than glass.

As discussed in, for example the International patent application WO94/19 186 (in the name of Pharmacia AB and Wipak Vihury Oy), it isconsiderable amount of technical problems that must be solved before apolymeric material with satisfying properties for storing parenterallyinjectible fluids is obtained. The material and container made thereofshould be capable of withstanding different sterilization techniqueswithout losing important characteristics, such as forming both an oxygenbarrier and moisture barrier against the environment. They shall becompatible with fluids to be stored, even after a long term storage andeven if the fluids contain lipophiic constituents that might lead tomigration and dissolution of unwanted compounds from the polymericmatrix. In addition, the materials must be possible to weld together andbe printable and maintain their flexibility and other mechanicalproperties, as well as their aesthetic appearance (i.e. transparency)after the sterilization procedure. It is also an important requirementthat such a container shall be sterilized as a final step, after beingfilled and assembled, to provide the highest possible safety for thepatients. It has been found that not even the highly sophisticatedmultilayer films according to the mentioned WO 94/19 186 will becompletely capable of meeting the highly rigorous requirements ofkeeping an oxygen barrier, when it is desired to store such sensitivefluids as lipid emulsions containing polyunsaturated fatty acids, forsuch a long time as several months in room temperature afterautoclavation in a single package.

However, so far it has not been regarded as possible to obtain all thedesirable properties combined in a single material and arrive with acheap, convenient construction which also is environment friendly andpossible to recycle by its manufacturer. For example, in the U.S. Pat.No. 5,176,634 to McGaw Inc., it is disclosed a flexible container havingthree chambers separated by frangible seals, in which diluents andmedicaments are separately stored until the seals are ruptured to mixthe contents together for delivery to a patient. if it is necessary toform a sheltering barrier against environmental oxygen for a storedproduct, this patent suggests the introduction of an aluminum foil as acomplement to the multilayered polymeric material of the container. Sucha mixture of metal and polymers in the same package, would however not,be desirable from an environmental viewpoint, since a recollection andrecycling of the material would be difficult. Furthermore, the U.S. Pat.No. 5,176,634 does not particularly teach containers that can be steamsterilized after their assembly and filling which is a precondition forcontainer systems for long term storage of parenteral nutrients intendedto substitute glass bottles. The container disclosed in U.S. Pat. No.5,176,634 obviously will be less suitable for separate storage of two ormore steam sterilized parenteral nutrients.

The U.S. Pat. No. 4,997,083 in the name of Vifor S. A. discloses aflexible three-chamber bag for separate storage of lipids, amino acidand sugar to be mixed within the bag and used parenterally. For themixing of the ingredients, transfer passages between the chambers areopened from the outside by the user. It is a drawback with this type ofcontainers that the mixing will be relatively slow and complicated,especially if all the chambers are filled to a high degree and liquidmust be pushed back and forth through the passages in order to completethe mixing procedure. If the lower mixing chamber is made large enoughto comprise the volume of all three constituents during the mixing, thelower chamber must be filled with a large head space which givesdisadvantages during the sterilization and storage of the products andleads to a poor utilization of the polymeric packaging material.Furthermore, the polymerized materials suggested to constitute theflexible bag in the U.S. Pat. No. 4,997,083 will not be sufficient tokeep the nutrients from oxidative degradation after long term storage.

The International patent application WO 95/26117 in the name ofFresenius A G discloses a more convenient type of multi-chamber bagwherein the partition between the chambers are made by a weak weldingpossible to rupture to immediately obtain a large mixing cross-sectionalarea without the risk of tearing away parts of the breakable means. Evenif this bag is made of a specifically designed multilayer foil having asealant layer capable of forming different type of weldings at differenttemperatures, it will not be able to form a satisfactory oxygen barrierto protect highly sensitive contents during long time storage afterautoclavation. Also its construction having filling tubes in thepermanent seams sealing the chambers constitutes a risk of leakages andmay cause problems if it is desired to have an additional airtightenclosure. This container therefore seems less suitable as athree-chamber container for joint separate storage of lipid emulsion,carbohydrates and amino acid solutions. Moreover, the exemplifiedincorporation of a paraffin oil in the multilayered material, wouldhardly be compatible with the storage of lipid emulsion when consideringthe risk for migration.

Also the British patent specification GB 2 134 067, in the name C. R.Bard Inc., discloses a flexible three compartment package havingrupturable seals between the chambers to enable mixing before dispensingof its contents. This package will, however not, for material reasons besuitable for parenteral medical products, such as infusible nutrients.

The U.S. Pat. No. 4,872,553 in the name of Material TechnologyEngineering teaches a single chamber container made of polymers,suitable for storing an amino acid solution aimed for parenteralnutrition, while the U.S. Pat. No. 4,998,400, assigned to the samecompany, discloses a method of making such a container. It is disclosedhow to fill and seal an inner primary container in an inert atmosphere,whereupon it is enclosed in an outer envelope together with a deoxidizerand autoclaved. The inner container consists of a linear low densitypolyethylene while the outer envelope consists of a three-layeredlaminated film formed of an outer nylon layer, a middle layer of anethylene-vinyl alcohol copolymer and an inner polypropylene layer. Sucha material will, however, not be possible to steam sterilize withmaintained quality at 121° C., as required by the EuropeanPhannacopoeia. However, not even such a container is likely to beentirely successful to provide a barrier for atmospheric oxygen afterautoclavation and during long-term storage, up to 12 months or more, ofmore sensitive fluids, like lipid emulsions based on triglyceridic oilsrich in polyunsaturated fatty acids and certain amino acids. Theteachings of U.S. Pat. No 4,998,400 indicates that the outer enveloperisks to lose important characteristics by the steam sterilization. Inone embodiment it is suggested that only the inner container shall beautoclaved. The inner container is thereafter cooled in an inertatmosphere and finally enclosed with the oxygen impermeable envelope.Such a process is not completely satisfying since it for rationalreasons is desirable to make the sterilization step on the finallyfilled and assembled container. In another embodiment it is suggestedthat the finally assembled and sealed container is autoclaved. However,in order to retain the oxygen barrier after the autoclavation an extradrying process must be introduced in order to remove absorbed moisturefrom outer envelope.

The European Patent Application EP 0 639 364 by Otsuka Pharm. FactoryInc. discloses another recent flexible multi-chamber bag for storage ofoxygen sensitive agents. This bag is preferably useful for storingdegradable powder formed drug and its diluent in separate chambers. Thechamber filled with the oxygen sensitive powder is covered with anoxygen barrier forming envelope which is sealed in a controlledatmosphere by weldings to the bag. A drawback with the containersexemplified in this application is that they may not withstandautoclavation after their final assembly.

It is obvious that the construction of a flexible multi-chambercontainer intended to substitute glass bottles for storing parenteralnutrients, such as lipid emulsions is a highly complex developmentprocess. A careful consideration must be taken to the capacity of thematerials of being autoclavable with maintained characteristics, totheir capacity of providing a barrier against environmental oxygen andwater vapor, while at the same time it must be easy to process to afunctional multi-chamber container, for example with conventionalwelding technology and comply with the demands of being possible torecollect and recycle in one single, simple process. For the parts ofthe container in contact with the stored, often lipophilic substances,it is a requirement that potentially hazardous agents must not beallowed to migrate into the parenteral product. Conventionally employedpolymers in medical packages, like polyvinyl chlorides (PVC), and otherpolymers containing migrating plasticizers therefore can not beconsidered. Nevertheless, these polymeric materials have a higherpermeability to oxygen than glass bottles which makes them unsuitablefor long-term storage of especially sensitive fluids. Moreover, thematerial must have an aesthetically attractive appearance with atransparency that do not deteriorate after sterilization and storage. Inaddition, the material must allow printing of instructions and fillinglevels without migration of the printing ink. It is also important thatthe material maintains all the mechanical characteristics, such asflexibility and strength, after the sterilization independently, if itis performed by steam or radiation. Besides the important materialproperties, the container must be convenient to handle when mixing thestored products and provide a high degree of safety for the patient,both when considering the manufacture of the container and its handlingby the user either in the home of a patient or at a hospital.

It is an object of the present invention to provide a flexible containerof substantially made of a polymeric material with an improved barrieragainst environmental oxygen and moisture which also is capable ofwithstanding sterilization by means of high pressure steam(autoclavation) or irradiation essentially without losing any suchbarrier capacity or other important characteristics includingflexibility or transparency, so even stored agents of high oxygensusceptibility may be stored for long periods with maintained integrity.

It is also an object of the present invention to provide a flexiblecontainer for separated long term storage of such agents that are easilyperishable when stored together in their final parenterallyadministerable form and provide the container with means for mixing suchagents aseptically within the container to an injectible fluid.

It is a particular object of the present invention to provide such acontainer for storing parenteral nutrition components separately, i.e. alipid emulsion, a carbohydrate solution and an amino acid solution, andsubsequently, just before parenteral administration, combine them to ahomogenous fluid nutrient mixture.

It is another particular object of the present invention to prolong thepossible storage period both in a cold environment and in roomtemperature for sensitive fluids aimed for total parenteral nutrition toovercome the problem of short shelf-life of such products.

It is still another object of the invention to provide a container withthe capacity of separately storing several components filled inready-made inner container which has a minimized number of potentialsites where leakages can appear.

It is a further object of the present invention to provide suchcontainers which are safe and convenient to handle and which minimizethe risks for erroneous handling and contamination during all the stepsnecessary to obtain a parenterally administerable fluid of apredetermined quality.

It is a still further object of the present invention to provide suchcontainers that are cheap and environment friendly by being to a highextent made of such polymeric materials which are possible to recollectand recycle together without an inconvenient dismembering of differentcontainer parts.

It is also an object of the present invention to provide a process formanufacturing such filled containers that are sterilized as a last stageafter being assembled and filled, wherein the filling process isperformed in a. manner that avoids permanent, potentially leakingfilling ports.

These objects of the present invention, as well as other obviousadvantages demonstrated in this text, are attained by the appendedclaims.

DESCRIPTION OF THE INVENTION

The container according to the present invention is aimed for improvedstorage of oxygen sensitive parenterally administerable agents andconsists generally of an inner, primary container enclosed in asubstantially oxygen impermeable outer envelope with an oxygen absorberwhich is capable of consuming essentially all residual oxygen after theouter envelope is sealed, and for sufficient period also the oxygenpenetrating said envelope. Both the inner container and the enclosingouter envelope are made of flexible and transparent polymeric materials.The inner container is made of a polypropylene containing flexiblepolymeric material compatible with lipophilic agents capable of formingboth permanent and peelable seals and the envelope is made of asubstantially water impermeable flexible multilayered polymeric materialcomprising a first outer substantially water impermeable polymeric filmwith oxygen barrier forming capacity, assembled with a second, innerpolymeric film with a supplementary oxygen barrier forming capacity.

An important feature of the assembled container is that is essentiallymaintains its characteristics of forming an oxygen and moisture vapor aswell as transparency and flexibility after being subjected tosterilization by steam or radiation.

The inner container can be a single or multi-chamber container filledwith one or several parenterally administerable agents. According to aparticular important embodiment of the present invention, the innerprimary container is divided into two or more chambers by one or moreleaktight seals which are possible to rupture by hand from the outsideof the container when the contents of the chambers are desired to bemixed to a homogenous fluid and administered to a patient by infusion orinjection. For this reason, the inner container is provided with a fluidcommunication port in its bottom through which the mixed product can bereceived and through which additional agents can be supplemented toeither to the mixed product or to the agent stored in the lower chamber.The port is attachable to conventional infusion devices and otherdevices useful for parenteral administration and will preferably haveseparate orifice for introduction and collection of fluid agents. Boththe inner container and the sealing envelope are made of specificallyselected polymeric materials which will be described in more detailbelow. As also will be explained in more detail below, the envelope isfinally sealed in a protected atmosphere and in the space between saidenvelope and the inner container an oxygen scavenger is placed.

The agents stored in the containers according to the invention arepreferably oxygen sensitive fluids or powders which otherwise loseactivity or suffer from degradation during extended storage. Example ofsuch agents are parenteral nutrients such as lipid emulsions containingoxygen sensitive polyunstaurated fatty acids, amino acids containingsensitive amino acids like cystein and many pharmaceutical agents whichlose activity when stored in dissolved or diluted form and consequentlymust stored as a solid powder (lyophilized) form or as a concentrateseparated from a diluent. Another example of agents that will benefitfrom storage in the inventive containers are such that must be keptseparate during sterilization by means of heat like solutions ofcarbohydrates and solutions of amino acids which together may formdiscoloring complexes.

The inventive multi-chamber containers are manufactured according to ageneral method, wherein a bag shaped sealed inner container is formedfrom a flexible polymeric material by welding together its polypropylenecontaining sealing layers. At least two leaktight chambers are formed bywelding at least one peelable seal seam possible to rupture by hand fromthe outside of the container. One side of the container is provided withtemporary openings to the chambers which are filled with theparenterally administerable fluids, whereupon the temporary openings aresealed again by welding permanent seams. The filled and sealed innercontainer is enclosed in an oxygen barrier forming envelope togetherwith an oxygen absorber which is sealed by welding in a controlledatmosphere. The so finally assembled is sterilized by means of steam orby irradiation.

The following detailed description aims to describe preferredembodiments and specific examples of containers and methods of theirmanufacture in accordance with the present invention, while illustratingappropriate alternatives. These examples are not intended to be limitingfor the scope of invention outlined by the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically shows a plan view of a container according to aspecific embodiment of the present invention.

FIG. 2a and FIG. 2b schematically show two examples of peelable sealseams according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As previously discussed there are several important requirements set ona material suitable for the inner container. It must be made of anautoclavable or radiation sterilizable polymeric material which iscompatible with the stored products. The material must be possible topermanently weld to a bag and weld to other polymeric details, such asthe mentioned saddle-formed port system, while also providing thepossibility of forming rupturable peelable seal seams during modifiedwelding conditions compared to the formation of permanent seams.Furthermore, the material should also be environment friendly andpossible to recycle with a simple process. The material should besubstantially impermeable for water vapor during steam sterilization,but need not be airtight according to the present invention, when anouter sealing envelope is used in combination with an oxygen scavenger.It would rather be an advantage if the material could permit an oxygentransfer so the oxygen scavenger can be able consume substantially allresidual oxygen dissolved in the stored fluids. If radiationsterilization shall successfully be applied on the container inaccordance with the International patent application PCT/SE95/00684,also the residual oxygen dissolved in the polymeric network of materialof the inner container must be removed. The material must have asuitable aesthetic appearance and be clearly transparent and not tend tobe discolored or opaque after sterilization. Finally, the material mustmaintain its flexibility and not become fragile or brittle aftersterilization and storage.

A polymeric material for the inner container having all the mentionedcharacteristics is preferably is a flexible film having a region with ahigher melt point designated as its outside and having a region withlower melt point designated as its sealing inside which can be sealedtogether by means of conventional welding tools to permanent or peelableseal seams. It is to be understood that the inner region is intended toface the stored agent or agents and can form both permanent seams anddifferent peelable seal seams when subjected to different weldingconditions or operations.

It is preferred that film is made of at least two different polymerlayers of which at least the inner sealant layer is based onpolyolefins, such as polyethylenes or polypropylenes of variousqualities which are chemically inert to the stored fluids, autoclavable,weldable and possible to recycle. The terms “polyethylenes” and“polypropylenes” are intended to include both homopolymers andcopolymers having such mentioned characteristics unless otherwise isspecified. Preferably, the sealant layer is based on polypropyleneincluding its copolymers with ethylene (propylene ethylene copolymer)and/or its mixtures with polyethylene.

However, since many conventional polyolefins, in particularpolypropylenes, often have an insufficient flexibility and a certainbrittleness, it is desirable to combine them with a polymer having anelastic property. In a specific embodiment according to the presentinvention it is therefore preferred to combine the polypropylene with asupplementary elastomer to improve its flexibility and resilience. Theelastomer can be comprised in neighboring layer of the film orcompounded with the polypropylene in the sealant layer. For multilayeredmaterials it is preferred to have an inner, sealant. layer comprising ahigh amount of polypropylene to benefit from its capacity of being inerttowards the stored fluids and for facilitating the manufacturing of acontainer by means of different welding techniques. It is especiallypreferred that this layer can form both leaktight, but controllablyrupturable, peelable seal seams at a predetermined temperature andpermanent highly consistent seams when welding it together withdifferent conditions, such as different welding temperatures or weldingpressures. It is also desirable to introduce a flexible polymericmaterial with a high melting point that provides the material with animproved stability at the high temperatures locally reached during thewelding, if such a material is comprised in a multilayered film, itshould be placed as an outer, release layer and additionally be easy toprint without migration of the printing ink. Suitable materials can befound among certain polyesters and copolymers thereof (copolyesters) andin particular cycloaliphatic polyesters.

A preferred material for the inner, primary container is made of amultilayered film comprising: a) an outer layer containing acopolyester, b) an inner sealant layer containing polypropylene, apropylene ethylene copolymer or a mixture of polypropylene orpolyethylene and c) an interior layer containing a thermoplasticelastomer. In such a film the sealant layer further may comprise athermoplastic elastomer which can be styrene-ethylene/butadiene-styreneblock copolymer (SEBS) or suitable alternative elastomer having theappropriate mentioned characteristics. A material that has been proofedto be especially suitable for this type of inner containers is EXCEL®brand of multilayered polymeric material from McGaw Inc., a multilayeredpolymeric material of about 200 micrometer thickness which is describedin the European patent 0228 819. EXCEL® brand of multilayered polymericmaterial has a multilayered structure substantially comprising:

a) an inner, sealant layer facing the medical fluid consisting of amixture of a polyethylene/polypropylene copolymer (FINA Dypro Z 9450)and KRATON® G1652 brand of styrene/ethylene/butadiene/styrene copolymerfrom Shell (a styrene/ethylene/butadiene/styrene (SEBS) copolymer);

b) a middle, tie layer of pure KRATON® G1652 brand ofstyrene/ethylene/butadiene/styrene copolymer; and

c) an outer, release layer of ECDEL® 9965 (or 9566 or 9967) from EastmanChemical Co. which is a cycloaliphatic thermoplastic copolyester (acopoly(ester ether), a condensation product of the transisomer of1,4-dimethyl-cyclohexanedicarboxylate, of cyclohexanedimethanol andhydroxyterminated polytetramethylene glycol).

The inner, sealant layer consists of a mixture of 80% copolymer ofpolyethylene and polypropylene with 20% of the elastomeric SEBScopolymer combined with minor additives of antioxidants and acidscavengers. The copolymer of polyethylene and polypropylene forms aninterpenetrating network with the SEBS-copolymer which provides for astrong seal. This mixture seals itself over a broad range oftemperatures and is capable of forming peelable seal seams of varyingstrengths, when welding in an interval of selected temperatures fromabout 85 to about 120° C. It has been demonstrated that welding at about110 to 120° C. forms peelable seal seams which are easy to rupture byhand. It also provides for a suitable steam barrier and will, as shownbelow, in the exemplifying part, satisfyingly withstand both chemicaland physical tests. The middle layer contains only the highly flexiblecopolymer KRATON® G1652 brand of styrene/ethylene/butadiene/styrenecopolymer with minor amounts of antioxidants. It contributes to theelasticity and the impact strength of the film. The outer layer ofECDEL® is flexible and printable with a high melting point of 200° C.and contributes to an improvement of the welding capacity of theassembled film. When using EXCEL® brand of multilayered polymericmaterial as the material for the inner bag formed container, it ispreferred that the saddle formed port system which shall be attached tothe sealant layer also contains polypropylene and preferably consists ofa mixture of polypropylene and KRATON® G1652 brand ofstyrene/ethylene/butadiene/styrene copolymer which is weldable to theinner layer of the EXCEL® brand of multilayered polymeric material film.A suitable mixture is about 60% polypropylene and 40% KRATON® G1652brand of styrene/ethylene/butadiene/styrene copolymer. A preferred touse the saddle formed port system as disclosed in the Swedish patentapplication 960 1540-9, also in the name of Pharmnacia AB.

An inner container made of the preferred EXCEL® brand of multilayeredpolymeric material film has excellent characteristics for beingautoclaved together with conventional parenteral nutrients. In addition,the EXCEL® brand of multilayered polymeric material film is surprisinglycompatible with lipophilic fluids. Even if its inner layer comprising aphysical mixture of polypropylene and the SEBS polymer, tests involvingits exposure to pure soybean oil (the main lipid constituent of thecommercial lipid emulsion INTRALIPID® lipid emulsion) has not given anyreasons to suspect the migration of potentially toxic agents. It will,however, have a relatively high oxygen permeability of about 1000 to1600 cubic centimeters/m², atm, day, when measured at a specifictemperature of 25° C. and 60% relative humidity and to comply with therequirements for long term storage of lipid emulsions and essentialamino acid solutions it must be combined with an outer surroundingairtight envelope and an oxygen absorber. Even if inner containers madeof EXCEL® brand of multilayered polymeric material constitute suitableembodiments for the present invention also other polyolefin based filmsmust be regarded as conceivable alternatives to use within the scope ofthe present invention, if they comply with the requirements mentionedabove. It is therefore an important alternative to provide innercontainers of a flexible, transparent film with a high degree ofcompatibility with lipophilic fluids from one or several layersconsisting essentially only of or entirely of one or several polymersselected from a group consisting polypropylene, copolymers of propyleneand ethylene, mixtures of polypropylene and polyethylene. For example, alayered film material comprising for example an inner sealant layer ofpropylene ethylene copolymer mixed with an elastomer, such as a SEBSpolymer attached to an outer layer of pure polypropylene which is coronatreated to be printable is a possible alternative material. Also a filmconsisting of an inner layer of ethylene containing polypropylene tiedto a pure corona treated polypropylene layer by a polypropylene with amodified tacticity, such as REXFLEX® film from Rexene or Dow is aanother conceivable alternative, as well as combinations of purepolypropylene layers having an improved elasticity and printability dueto modifications in their molecular configurations or due to physicalprocessing. For example, with metallocene type catalysts, a higher levelof control of the stereoregularity of polypropylene chains can beobtained, as disclosed in Macromolecules, Vol. 28, 1995, pages 377 1-8:W J Gauthier et al. This can yield profound effects on the physicalproperties of the material and impart e.g. highly flexible orelastomeric polypropylenes which can be included as future alternativesto EXCEL® brand of multilayered polymeric material. All suchpolypropylene based materials should be regarded as alternativeembodiments of materials selected for the inner container, if theycomply with the requirements set above.

As discussed in relation to the selection of material for the innercontainer, the material of the surrounding envelope must meet a numberof demands to replace glass bottles. It must most importantly provide ahigh barrier against atmospheric oxygen. admitting an oxygen inflowpreferably less than about 30 cubic centimeters/m², atm, day, whenmeasured at a specific temperature of 25° C. and 60% relative humidityand more preferably less than 15 cc/m², atm, day and most preferablyless than 5 cc/m², atm, day, when measured at the same conditions. Itmust be steam sterilizable at 121° C. for at least 30 minutes, whilealso having the capacity to withstand sterilization by irradiation toimprove on existing aseptic overwrapping techniques. A conventionalaluminum foil would meet such requirements, but will have the drawbackof not being transparent to enable a visual inspection of the integrityof the stored material and for example an oxygen indicator. Furthermore,the envelope material must be strong and flexible, have a low impact onthe environment and only contain such additives with the lowest possibletendency to spoil or interfere with the stored material by migration.The criterion of forming a barrier against oxygen can also be met bypolyvinylidene chloride (PVDC), but it will, however, not be possible tosteam sterilize and will not meet the demands of being environmentfriendly. As earlier discussed in the International patent applicationWO 94/19 186, it was attempted to construct a multilayer film forpackaging and autoclaving parenteral agents. This film was intended tosupport the oxygen barrier capacity of a poly(ethylene)-vinyl alcohollayer (EVOH) by introducing a water resistant and moisture absorbingouter structure to protect the EVOH-layer during the steamsterilization. Unfortunately, not even this multilayered film wascapable to keep a satisfactory long time barrier against oxygen afterits autoclavation. It was therefore highly desirable to improve such afilm by adding to the EVOH-layer a protecting structure which not onlywas steam impermeable, but also could contribute to the oxygen barrier.

According to the present invention, it has been surprisingly found thatif a first outer substantially water impermeable polymeric film withoxygen barrier forming capacity is assembled with a second, innerpolymeric film with a comparatively higher oxygen barrier formingcapacity at 25° C. at 60% relative humidity, a multilayered materialsuitable for forming an outer sealing envelope for the inventivecontainer is obtained which can maintain such a high oxygen barrier asless than 5 mi oxygen per m², atm and day at a normal relative humidity,even after autoclavation and yet comply with the requirements set above.

Preferably, the outer film comprises a metal oxide coated polymericlayer connected to a second, inner film comprising an oxygen barrierforming polymeric layer. It is preferred that the outer film comprises ametal oxide, such as an oxide of silicon and/or aluminum and/or titaniumtogether with at least one polymeric material, while the inner filmpreferably comprises an EVOH layer. Preferably, the outer film comprisesa layer of polyethylene terephtalate coated with the metal oxide, whilethe inner film comprises at least one layer containing polypropylene.The outer film may comprise a second layer of polyethylene terephtalate(PET). In such cases, a first outer layer of polyethylene terephtalate(PET) is coated on one side with a metal oxide which is bound to asecond layer of polyethylene terephtalate (PET). According to a specificalternative, both sides of a PET-layer is coated with metal oxide. Theouter film can suitably contain a polyethylene terephtalate (PET) layercoated with a metal oxide of about 10-30 p.m. preferably about 25 p.m.thickness tied together to the inner film of about 50-200 p.m.preferably about 100 p.m thickness which preferably contains an EVOHlayer tied together to surrounding polypropylene based (PP) layers (madeof polypropylene, various copolymers of propylene and ethylene ormixtures thereof) in a conventional manner to obtain a multilayeredmaterial of the principal structure PET-metaloxide/glue/PP/tielayer/tie/EVOH/ tielayer/PP. This material will providethe oxygen barrier forming EVOH layer with an effectively protectingshield against moisture penetrating the polypropylene during steamsterilization and storage which otherwise will impair its subsequentbarrier forming capacity. At the same time, the glassy, outer film willcontribute to the oxygen barrier. The inorganic glassy metal oxidematerial consists of a thin metal oxide layer having a thickness ofabout 200 to 1200 Å and is deposited on a smooth polymer surface by aconventional technology, for example described in the European patentspecification EP 0460796 (RI. Du Pont De Nemours & Co.), whereinsuitable PET-glass films are disclosed. The metal oxide may also bedeposited on both sides of the film or a further PET layer can be added,so films of the structure glass-PET-glass-glue/PP/EVOH/PP orPET-glass/glue/PET/PP/EVOH/PP are obtained.

The glue binding the two films together is of a type conventionally usedin adhesive bonding of multilayered polymer structures with a suitablylow tendency to migrate. An especially suitable film is composed ofPET-aluminum oxide/gluefPET/glue/tie/EVOH/ie/PP. In the followingexemplifying part, it is demonstrated that it has excellent propertiesfor constituting a protecting outer envelope in container for safelystoring parenteral nutrients.

The oxygen absorber according to the present invention preferably isiron containing and dependent on water for its oxygen consumption, asdescribed in the International patent application PCT/SE95/00684 in thename of Pharmacia AB. It is preferable that the ferrous oxygen absorberalso can consume a certain amount of hydrogen sulfide degraded fromsulfur containing amino acids, such as cystein in a stored solutioncomprising essential amino acids, as is disclosed in the German patentDE 42 33 817. The oxygen absorber shall be capable to withstand asterilization procedure selected from steam sterilization andsterilization by means of irradiation without being impaired. The oxygenabsorber can either be present in the container as a sachet or it can becompounded as a part of a multilayered film. It is preferred to use anoxygen absorber having a ferrous oxygen scavenging composition enclosedin one or several sachets or tray-like carriers placed close to thesaddle-formed port system of the inner, filled container during theenclosure with a surrounding airtight envelope in a controlledatmosphere. For the preferred type of oxygen absorber, it is thereforeimportant that there is a source of water present, either in the oxygenscavenging composition or elsewhere in the space wherein it shall exertits activity.

Certain oxygen absorbers demand an atmosphere of at least 80% relativehumidity (at 25° C.) for a maximum activity and would therefore requirea high humidity in the closed space between the inner container and theenvelope to ensure a correct function which typically is above according60% in containers according to the present invention. This type ofmoisture dependent oxygen absorbers are preferred according to thepresent invention. The skilled person will have no difficulties inobtaining suitable oxygen absorbers in an appropriate amount whendesigning a container according to the present invention. An estimationof a necessary quality and amount can easily be performed from itsoxygen predetermined consuming capacity when given values of thecontainer, for example, of the volume of the stored material and theoxygen barrier capacity of the surrounding envelope. For example, if thetotal capacity of the oxygen absorber is at least 100 ml pure oxygen,this value must be higher than the amount expected to penetrate theenvelope through a given area during a given time if the envelope ismade of a material having an oxygen permeability of not exceeding 5 mloxygen per m², atm and day at a normal relative humidity. An example ofa suitable oxygen absorber, according to the present invention, isAGELESS® FX200PA ferrous oxygen absorber available from Mitsubishi.

In the specific embodiment illustrated in FIG. 1, the container has anouter sealing envelope 10 and an inner three-chamber container 30 filledwith three different parenteral fluids. In the space between theenvelope and the inner container, an oxygen absorber 20 is placed. Inthis space, also an oxygen indicator showing inadvertently penetratedoxygen from leakages, an indicator demonstrating a correct sterilizationand other conditions optionally can be placed. Such indicators must, ofcourse, be able to withstand the sterilization step, either with steamor radiation and they must not cause migration of toxic or potentiallyhazardous substances to the stored products.

The inner container shown in FIG. 1 is bag formed and provided withthree parallel chambers 31, 32, 33 which may have the same or differentvolumes dependent on the desired amount of the stored product. The innercontainer is illustrated as being provided with a handle part 34 in itstop to facilitate conventional administration from a hanging position.The bottom of the container is provided with a port system 35 which canbe a conventionally formed saddle port welded to the container materialduring the manufacture. A preferred port system which is designed to bemore easily sterilized is described in a parallel, as yet unpublished,Swedish patent application.

The port system has an outlet port 36, through which fluid communicationto a patient in need of fluid therapy can be established by conventionalinfusion devices which, however, not are discussed in more detail.Through an inlet port 37 of the port system, it is possible to introducean additional agent to the fluids of the container in any desiredmoment. Such agents are typically supplementary drugs or nutrients ormicronutrients which can not be stored together with fluids of thecontainer.

In this embodiment, the three chambers 31, 32 and 33 are filled withthree different parenterally administerable nutrients in fluid formswhich, just before their administration to the patient, shall behomogeneously mixed together to form a total parenteral nutrition (TPN)solution. To enable such mixing at will, the chambers are divided bysuch seams that can readily be ruptured by the user from the outside ofthe container. The two seams 50,50′ separating the chambers aretypically formed by peelable seal weldings in the container which arehighly leak tight, but possible rupture by a predetermined motion of theuser. Peelable seals or weak weldings belong to a well-known techniquein the art processing of polymers and the conditions about theirformation and characteristics are described more in detail in U.S. Pat.No. 5,128,414 or in the European patent specifications EP 0 444 900 andEP 0 345 774 which documents hereby are incorporated as references. Aparticularly preferable construction of the welded peelable seal seams,suitable for a container according to the present invention, will bediscussed in greater detail below.

In the specific embodiment of a container according to FIG. 1, onechamber contains a carbohydrate solution comprising glucose, one chambercontains a lipid emulsion typically comprising 10-30% (w/w) of a lipid,such as INTRALIPID® lipid emulsion of Pharmacia AB, and one chambercontains an amino acid solution such as VAMIN® amino acid solution fromPharmacia AB, if suitable comprising the essential amino acids. Suchparenterally administerable nutrients and their appropriate additivesfor giving total parenteral nutrition and/or complementary drug therapyare described in more detail in other documentation, such as theEuropean patent application 0 510 687 in the name of Green Cross Corp.which is incorporated as a reference in its entirety. When suitable forclinical reasons, each of these three nutrients can comprise furtherconstituents, such as trace elements, electrolytes, vitamins, energysubstrates, supplementary therapeutic agents and agents supporting themetabolization of said nutrients. However, it must be carefully analyzedfor each constituent, in which chamber it shall be stored withmaintained integrity and minimal interference with the selectednutrient.

The designation of the chambers 31,32,33 for the three mentionednutrients has been done after careful consideration of both convenienceand safety aspects. For such a reason, it is preferred that either theamino acid solution or the lipid emulsion is contained in the bottomchamber 33, since, if the user, for some reason, would be unsuccessfulin correctly performing the mixing procedure, the infusion of a pureamino acid solution or a lipid emulsion leaves the patient unaffectedcompared to an accidental infusion of pure glucose solution which couldlead to unwanted side effects, for instance, if the patient suffers fromcomplications related to diabetes. It is therefore preferred that thecarbohydrate solution that the top chamber 31 is filled with thecarbohydrate solution which also is of advantage when considering itsrelatively larger volume can be used to exert a sufficient pressure torupture the upper peelable seal 50 when mixing the nutrients.

According to one embodiment, the middle chamber 32 contains the lipidemulsion, so it may serve as a visual or optical leak detector if anyleakages in the seals between chambers will appear during the storage,while the lower chamber 33, facing the port system is designated for theamino acid solution. As an alternative embodiment, the lower chamber 33may contain the lipid emulsion having the smallest volume. This is willgive the filled chambers a similarly shaped volume extension and heatpenetration during the steam sterilization in order to obtain a similartemperature gradient in all the three chambers.

However, in certain applications the convenience of opening the chambersfor fluid transfer by rupturing a peelable seal are given priority. Forexample, it might be desired to have the constituent with the largestfluid volume designated for the top chamber in order to use its mass forrupturing the peelable seal seams, regardless of the contents of thechambers. It should also be understood that other chamber configurationsthan the three parallel chambers shown in FIG. 1 is conceivable withinthe scope of invention.

Besides parenteral nutrients it is conceivable to store a large numberof other parenterally administerable products in a container accordingto the present invention, also such that are in solid powdered orlyophilized forms can be stored together with diluents and otherparenteral fluids when appropriate for stability reasons.

A container according to the present invention is preferablymanufactured with an inventive method wherein a flexible polymericmultilayered material is introduced in bag forming station where a bagshaped sealed inner container is manufactured by welding togetherpolypropylene containing sealing layers of the material and whereoptionally at least two chambers are formed by welding at least onepartitioning peelable seal seam at a lower temperature. During the bagforming process a side of said inner container is provided with at leastone temporary opening, whereupon the inner container is filled with atleast one parenterally administerable fluid through said temporaryopening. The temporary opening at the side of said inner container canthen be sealed by welding permanent seams and the filled and sealedinner container is enclosed in an oxygen barrier forming envelopetogether with an oxygen absorber and the so final sealed container issterilized.

Preferably, the polymeric material for the inner container is in theform of thin flexible sheet in a suitable, predetermined size whenintroduced to the bag forming process. The sheet is first attached to asealed port system for fluid communication, preferably of thesaddle-formed type described above, whereupon the port system is weldedto the sheet. When attaching the port system the sheet may first bepenetrated by a suitable tool, so to form one or several orifices in thesheet corresponding to the number of orifices of the port system.Preferably, two such orifices are made to correspond with an exit and aninlet port.

A bag shaped sealed inner container with two identical faces, a bottom,a top and two sides is formed around the bottom with the attached portsystem in its bottom by welding together the polypropylene containingsealing layers of the material by conventional welding tools, thusforming two side seams and a top seam.

Although the above described forming of the bag is preferred accordingto the present invention, it would in certain applications beconceivable and regarded as a part of the present invention, to, as analternative, start the manufacture from a blown tubular parison ofpolymeric material and by welding form permanent sealing seams in itstop and bottom and provide for the attachment of a port system in itsbottom seams. Filling ports for the chambers must thereby be attachedduring said welding procedure. This type of manufacturing processsuitable for preparation of inner containers having one or two chambers,but less suitable if three or more chambers are preferred. Themanufacturing process may as another alternative start from two sheetswhich are welded together with four seams around to form a bag shapedinner container having a sealed port system for fluid communicationwelded in its bottom seam. Such an inner container can be provided withpeelable seal seams between its storage chambers and alternativetemporary filling ports, as disclosed below.

If two or more chambers are desired for separate storage of two or moreagents, at least one leaktight peelable seal seam is formed aspartitions between the chambers of the inner container which arepossible to rupture by hand in a predetermined manner. By welding at aspecific, lower temperature compared to the previously mentionedpermanent weldings such peelable seals can be manufactured. As will bediscussed below in greater detail the peelable seal seams can be madewith a specifically designed zone to obtain an initial rupturing pointto facilitate their manual opening when it is desired to mix the storedcontents within the container.

To enable filling of the inner container it is provided with at leastone temporary filling port in the side of the bag shaped inner containerwhich subsequently to completed filling is sealed with a permanentlywelded seam. The filling is preferably performed in a controlledatmosphere and in connection with a blast of an inert gas, such asnitrogen or helium, to remove air from the inner container.

According to a first embodiment of the manufacturing method, one orseveral specific provisional filling tubings designated for one orseveral fluid agents are attached in the seam of the inner containerduring the welding. The chambers can then be filled with one severalparenterally administerable fluids by through the provisional fillingtubings by sealing connection to filling nozzles of a conventionalfilling equipment. After the filling is completed, the side providedwith filling tubings attached to the seam is cut off, whereupon the sideis re-sealed with a permanently welded seal.

According to a second embodiment of the manufacturing method, one sideof multi-chamber inner container is sealed by means of a weak weldingwhich can be ruptured by means of the filling equipment in order to format least one temporary opening in the side seam. Preferably, the weakside seam is welded so as two sleeves are formed from the edges of thesheet outside the weak seam to enable the filling equipment to open theseam by a peeling. For example the filling equipment can be providedwith one or several twistable rods which opens the seam by a peelingmotion in connection with that one or several filling nozzles areintroduced in the inner container from its side, preferably in acontrolled atmosphere in connection with a blast of an inert gas, asmentioned above. After the filling is completed the filling nozzles areremoved and the side of the inner container is re-sealed with apermanent welding seal. It is to be understood that alternative meansfor open the peelable seal to form temporary opening for filling can beemployed, for example the filling nozzles may provided peeling means inthe form of protruding devices which may perform a twisting, peelingmotion. After filling and removing the nozzles, the side of innercontainer is welded and sealed by a permanent seam.

According to a third embodiment at least one filling orifice is formedin a side seam of the container with a shape corresponding to a fillingnozzle of the filling equipment in order to provide a sealing connectionbetween the orifice and the nozzle during the filling procedure. Suchfilling orifices can be formed by directly shaping the flexible materialto an orifice having a form corresponding to the nozzles or by attachinga separate orifice to the side of the inner container when forming aside seam.

The level of filling or amount of head space in each chamber must becarefully controlled. It is desired that the filling level of eachchamber is, if not identical, at least comparable which is advantageousfor obtaining the same heat penetration of the filled products duringthe heat sterilization. When desiring the level of filling it must beconsidered that a large head space volume from a low filling level mightlead to that a sensitive lipid emulsion partially breaks up if thecontainer is unintentionally shaken during its handling. A small headspace volume from a high filling level will lead to difficulties inreading a correct fluid level in the container.

The completely assembled and filled inner container is enclosed in anoxygen barrier forming envelope together with an oxygen absorber andoptionally together with one or several visual indicators. The finallyassembled container can now be sealed by permanently welding theenvelope together in tool operating in a controlled, if desired, inertatmosphere. The container can now be sterilized by means of steam atabout 120° C. (autoclavation) or by sterilizing gamma radiation. Thedescribed inventive manufacturing method is advantageous for industrialproduction of parenteral nutrients and minimizes the utility of acontrolled atmosphere and the use of inert gases is reduced to one stepwhere the inner container is filled which is highly resource saving andguarantees a simplified production process. Furthermore, the fillingemploys provisional, openings at the side of the container whichminimizes the risk for leakages conventionally experienced in connectionwith permanently attached filling ports. Such a filling also gives thebenefits of a smaller enclosing envelope and a shorter autoclaveprogram.

The previously described peelable seal seams, serving as leaktightpartitions between the chambers during storage in the inner container,must be easy to open manually by the user in a simple predeterminedmanner from the outside of the container, preferably without removingits enclosing envelope. According to the present invention, the peelableseal seams are preferably straight seams provided with a rupture zone.

According to the embodiments demonstrated in FIG. 2a and FIG. 2b, therupture zone of such a peelable seal seam comprises a point where twostraight seams meet in angle. A small or sharp angle will be easy torupture by the user, but it will at the same time create a risk forunintentional opening when handling the container. Such a seam willenable a surprisingly easy rupturing or peeling process by providing aconcentration of the opening forces on a single point in the angle ofthe seam, whereupon it can be easily peeled apart. In contrast, a verylarge angle will provide a seam that is difficult to open. It is desiredto obtain a optimized angle which gives initial opening resistance ofthe seam while providing a successively reduced resistance as theopening proceed towards the sides of the container, when the fluidenters between the foils and separates them. When having a sufficientlylarge angle, the opening force and the foils will become almostperpendicular to the seam which facilitates the opening process. A toosmall angle might also lead to the appearance of hole in the middle ofthe seam, but no further opening of the seam, since the lines of forceson the opening point will have tangential direction and not contributeto the opening of the remaining seam. For embodiments of FIG. 2a and 2 band similarly formed seams, the angle of the seam (or in the projectionof the seams when having curves in the seam) is at least 90°.Preferably, the angle is less than about 170° and more preferablybetween about 110° to 160°. According to specifically preferredembodiments, the angle is between about 120° to 140° and according totwo experimentally well functioning embodiments about 120° or about140°. Both rupture zones demonstrated in FIG. 2a and 2 b will providefor local reductions in the opening force which considerably facilitatesa manual opening of the peelable seals. As also demonstrated in FIG. 2athe rupture zone can comprise a curved part of the seam. It may also beadvantageous to round one or several sharp sections of the seam in orderto control the manual forces required for the rupture process. The seamsaccording to FIG. 2 have will provide easy peelable openings in acontainer having a length of 450 mm including a handle part and a widthof 300 mm, as illustrated in FIG. 1. Such seams can readily be opened bydifferent handling techniques which are intended to be a part of theinstructions of the container. The seams are suitably opened while stillhaving the outer enclosing envelope protecting the inner container whichgives the benefit of prolonged protection.

The rupture zones preferably are positioned in the middle of the seam,so it can be successively opened from the middle towards the sides,since this may enable a highly reproducible opening procedure by theuser from the outside of the bag. The rupture zone typically has anextension of less than half the entire seam, preferably less or equalthan about 40% of the seam and more preferably less than about one thirdof the seam length. The width of the weak seal seams are typically lessthan 10 mm and preferably about 3 to 8 mm and exemplified as about 6 mmin the seams demonstrated in FIG. 2a and 2 b. Alternative designs of therupture zone to what have been exemplified in FIG. 2a and 2 b anddiscussed above are conceivable to the skilled person if they can complywith the demands of being leaktight during storage and transportationand yet are readily opened manually according to simple instructions.For example, the peelable seal seam can be made entirely straight and byvarious means such as variations in the welding pressure and/ortemperature and differently shaped welding tools.

Suitable peelable seal welding temperatures for the above mentionedEXCEL® brand of multilayered polymeric material in the inner containerare in the range of 106-121° C. using a pressure of about 315±20 N ofthe welding tool for 2-10 second with gauge meter of about 0.3 mm. Suchseams are demonstrated to be suitably leaktight after being subjected toconventional mechanical package tests and are objectively easy to open,also after the container has been subjected to steam sterilization at121° C. for about 20 minutes.

A first preferred opening procedure is to gently roll up the containerfrom the upper side (the side opposite to the attached port system) andthereby make use of the volume of the largest chamber, suitablycontaining a glucose solution, to exert a pressure large enough torupture the seal in its weakest point and peel apart the seam towardsthe sides of the container. Another preferred way of opening the seal isto pull the front and the rear walls of the inner container apart fromone another by a careful pulling motion so a rupture is formed in theweakest spot of the seal which thereby may be easy to peel apart.

When making an inventive container ready for use, its peelable sealseams can be ruptured in a predetermined manner as discussed above. Thestored parenteral agents can thereby be mixed in a mixing chamberconstituting the entire volume of the inner container, if necessary thecontainer can be gently agitated to a homogenous fluid suitable forimmediate administration. For the alternative of mixing a separatelystored lipid emulsion, an amino acid solution and carbohydrate solution,it can be readily mixed into a TPN-solution in a highly convenientmanner. The enclosing envelope can be removed and if desiredsupplementary agents can be introduced through the port system to beadmixed to container. The inner container is now completely ready to beused and, if desired hanged on a rack by means of the hanger or otherready made means of the container before connecting to a patient, forexample by using a conventional infusion device after penetrating theoutlet port of the port system. The inventive container is aimed to beadapted to a large number of conventional infusions sets and suchdetails will not be discussed here in further detail, since they are nota part of the present invention.

EXAMPLE 1

This example shows the stability of INTRALIPID® lipid emulsion 20% in a500 ml EXCEL® brand of multilayered polymeric material inner containerwrapped in an enclosing envelope made of the layers PET-aluminumoxide/glue/PPIEVOH/PP given the trade name Oxnil (Pharmacia & UpjohnAB), together with an oxygen absorber (AGELESS®D FX100 from MitsubishiGas Co.) INTRALIPID® lipid emulsion 20% in a 500 ml glass bottle is usedas a reference.

INTRALIPID® lipid emulsion 20% stored in a container according to thepresent invention was compared with INTRALIPID® lipid emulsion 20%stored in a glass bottle at 25° C. and 60% relative humidity for 18months. After 18 months storage the pH values and the amounts of freefatty acids (FFA) and lysophosphatidyl choline (LPC) were tested. Themean droplet size was measured according to conventional routinesemployed by manufacturers of intravenous lipid emulsions in thepharmaceutical industry.

Months Peroxides FFA Mean Droplet Storage (mEq/l) pH LPC (mg/ml)(mmol/L) size (nm) Emulsion stored 12 0.0 7.2 0.69 2.3 387 in glass 180.1 7.1 0.84 2.7 348 Emulsion stored in 12 0.0 7.5 0.74 2.2 334 polymercontainer 18 0.0 7.3 0.83 2.7 335 (Mean values of five batches)

(Mean values of five batches)

The initial pH-values were about 8.0-8.4 and decreased after storage, aswould be expected due to an increase in free fatty acids (FFA) andlysophosphatidyl choline from hydrolysis of triglycerides andphospholipids. A minor weight loss was measured on the polymercontainers about 0.6% after 12 months and about 0.8% after 18 months.

This test demonstrates that the container according to the presentinvention exhibits an entirely comparable storage capacity in relationto glass containers in protection against degradation and physicalchanges that deteriorates the emulsion quality. Emulsions stored in theinventive container will consequently have a shelf life of at least 18months when stored during normal conditions.

EXAMPLE 2

The oxygen barrier forming capacity of the material selected as anenvelope for the inner filled container is tested.

The envelope material consists of a multilayered polymer structure ofPET-metal oxide/glue/PP/EVOH/PP as disclosed, above in Example 1.

In order to determine the benefit of the PET-metal oxide layer, such afilm (Film 1) is compared to a conventional PP/B VOH/PP(PP=polypropylene and EVOH=((poly)-ethylene vinyl alcohol) film (Film 2)for oxygen permeability measured in ml oxygen penetrated per day and m²,at two different temperatures and at 75% relative humidity. Thepermeability tests were performed with standard Mocon permeabilitymeasurements.

Film 1 (ml/day, m²) Film 2 (ml/day, m²) 25° C. 1.1  4 40° C. 2.9 23

It is obvious that the PET-metal oxide containing film (Film 1) complieswith the requirements of having an oxygen permeability of less than 5mI/day, m².

The PET-metal oxide film was also subjected to chemical and mechanicaltests after being steam sterilized according to the EuropeanPharmacopoeia and exaggerated test at 121° C. for 60 minutes. It wasfound the material also fulfills the demand of the EuropeanPharmacopoeia when considering the migration of components from thefilm, as well as having excellent values in terms of absorbance,alkalinity/acidity, oxidizable substances and appearance of the storedsolution.

EXAMPLE 3

This example aims to study the mixing properties into a safelyadministerable TPNsolution of one batch of lipid emulsion stored in acontainer according to the present invention for 12 months at +5° C. and+25° C.

INTRALIPID® lipid emulsion 20% filled in 500 ml inner containers made ofEXCEL® brand of multilayered polymeric material were stored with anoxygen absorber in an enclosing envelope made of the layers PET-metaloxide/glue/PPIEVOHIPP, as disclosed in Examples 1 and 2.

The so stored lipid emulsion was brought together with a 1000 ml aminoacid solution (VAMIN® amino acid solution 14 g N/I) and 1000 ml glucosesolution (Glucose 20%). 10 ml ADDIPHOS® phosphate solution were added tothe glucose solution. SOLUVIT® vitamin preparation reconstituted inVITALIPID® lipid preparation was added to the lipid emulsion andconventional electrolytes (ADDAMEL® electrolyte, ADDEX® electrolyteNaCl, ADDEX(® electrolyte KCI and CaCl₂ 1M) to the amino acid solution.After gentle agitation, the mixture was transferred to a 3 liter IV bagwith its air expelled which was agitated thoroughly to ensure propermixing. Part of the bag was dispensed into a glass bottle for analyzeday 0 and day 6.

The IV bag with its remaining content was stored flat horizontally for 6days at cold temperature about +5° C. followed by one day in roomtemperature about +25 ° C. when it was hung vertically. The glassbottles were stored at room temperature for 7 days and 24 hours,respectively. To be considered physically stable the admixtures mustpass the inspection after 24 hours storage at room temperature and 6days storage at cold temperature followed by one day at roomtemperature.

Mean droplet size (μm) (D(4,3), Malvern mastersizer 0 days 6+1 days  +5°C. 0.37 0.39 +20° C. 0.37 0.38

The appearance of the emulsions was approved according to a conventionalvisual inspection performed as a standard routine by experiencedemulsion manufacturers. A cream layer varying between 1 and 3.5 mm waspresent in all admixtures. It was, however easily redispersed by gentleagitation. There were no significant change in mean droplet size or dropsize distribution after 6+1 days storage.

The fraction of droplets less than 5.29 p.m were 100% in all sampleswhen measured with a Malvern Mastersizer and there were no dropletslarger than 8 p.m in any of the samples according to an investigationwith a phase contrast microscope.

The admixtures tested were satisfactory physically stable accordingemulsion appearance.

EXAMPLE 4

The mixing properties of INTRALIPID® lipid emulsion 20% (20% soybean oilfat emulsion from Pharmacia AB), filled and steam sterilized in threechamber inner containers made of EXCEL® brand of multilayered polymericmaterial, was compared to INTRALIPID® lipid emulsion 20% heat sterilizedand stored in a glass bottle.

Each three chamber container was purged with filtrated nitrogen twotimes immediately prior to the filling and 500 mi nonsterile INTRALIPID®lipid emulsion was transferred into the middle compartment from glassbottles. The other compartments were filled 614 and 1193 ml water forinjection, respectively. The filled and sealed container was placed inan envelope made of PET-metal oxide/glue/PP/EVOH/PP, as mentioned inearlier examples, with an oxygen absorber between the outlet and theinlet port of the saddle formed port system. Before sealing theenvelope, it was evacuated in a Multivac before nitrogen was flushedinto the envelope to a suitable gas volume for sterilization, whereuponit was sealed. The container was thereafter autoclaved corresponding to17 to 20 minutes at 121.1° C. The reference glass bottle was autoclavedcorresponding to 12 minutes at 121.1° C., according to a regularmanufacturing process. The mixing was carried out under asepticconditions in the same order is if mixing was performed in a threechamber container. A 17.2% glucose solution was transferred to themixing vessel under nitrogen protection, whereupon lipid emulsions(INTRALIPID® lipid emulsion 20%) treated as above, was added and aftergentle shaking amino acid solution (VAMIN® amino acid solution 18 withelectrolytes)was admixed and agitated. The admixtures were dispensedinto sterile infusion bottles under nitrogen protection. After sealingthe bottles, they were stored at ambient temperature (about 25° C.) fortwo days or at about 5° C. for 6 days followed by 2 days at about 25° C.

The admixtures were tested for creaming (visual inspection of the creamlayer), emulsion appearance (visual inspections of oil droplets onsurface and glass walls) and mean droplet size and droplet sizedistribution (Malvern Mastersizer)

No obvious difference could be found in creaming or emulsion appearancebetween the different admixtures.

The following mean droplet sizes in p.m were found for admixtures withlipid emulsion from glass bottle and mean values from three differentbatches stored in the polymer container, respectively,:

Storage time/temp. glass bottle polymer container 48 h at about 25° C.0.40 0.43  6 days at 5° C. and 0.42 0.44 48 h at 25° C.

The results show that lipid emulsion autoclaved in three chamber polymercontainers maintain their mixing properties and do not physicallydeteriorate, when compared to emulsions autoclaved in glass bottles.

By its high integrity of the stored constituents, its specific chamberconfiguration in multi-chamber embodiment and facilitated mixingprovisions, the container considerably improves both the safety and theconvenience for the patients dependent on long-term administrationregimens when compared both to conventional mixing systems consisting ofindividual glass bottles and comparable flexible container with ashorter shelf life. Even the most oxygen sensitive amino acids will nowbe possible to comprise in during long term storage by using theinventive containers. The inventive containers are also highly suitablefor being industrially manufactured in a large scale by a forming,filling and sealing procedure of the inner containers which subsequentlyare assembled to the final container and sealed in an outer envelope,with a minimum of requirements of an oxygen deprived atmosphere, beforefinally being sterilized and stored.

We claim:
 1. A method of preparing a flexible transparent container forimproved storage of oxygen sensitive parenterally administerable agentswherein the container comprises an inner, primary container enclosed ina substantially oxygen impermeable outer envelope with an oxygenabsorber, capable of consuming essentially all residual oxygen after theouter envelope is sealed, as well as the oxygen penetrating saidenvelope wherein: (i) the inner container is made of a polypropylenecontaining flexible polymeric material compatible with lipophilic agentscapable of forming both permanent and peelable seals; (ii) the envelopeis made of a substantially water impermeable flexible multilayeredpolymeric material comprising: a) a first outer substantially waterimpermeable polymeric film with oxygen barrier forming capacity,assembled with b) a second, inner polymeric film with a supplementaryoxygen barrier forming capacity; and in that the container essentiallymaintains its characteristics after being subjected to sterilization bysteam or radiations, the method of preparing comprising the steps of: a)introducing a flexible polymeric multilayered material and forming a bagshaped sealed inner container by welding together its polypropylenecontaining sealing layers and optionally forming at least two chambersby forming at least one partitioning peelable seal seam; b) providing aside of said inner container with at least one temporary opening; c)filling the inner container with at least one parenterallyadministerable fluid through said temporary opening; d) sealing thetemporary opening at the side of said inner container by weldingpermanent seams; e) enclosing the filled and sealed container in anoxygen barrier forming envelope together with an oxygen absorber; and f)sealing the envelope by means of welding and finally, sterilizing thecontainer.
 2. The method according to claim 1, wherein the inner primarycontainer is made of a multilayered film comprising; a) an outer layercontaining a copolyester; b) an inner sealant layer containingpolypropylene, a propylene ethylene copolymer or a mixture ofpolypropylene or polyethylene, and c) an interior layer containing athermoplastic elastomer.
 3. A method of preparing a flexible transparentcontainer, the method characterized by the steps of: a) introducing aflexible polymeric multilayered material and forming a bag shaped sealedinner container by welding together its polypropylene containing sealinglayers and optionally forming at least two chambers by forming at leastone partitioning peelable seal seam; b) providing a side of said innercontainer with at least one temporary opening; c) filling the innercontainer with at least one parenterally administerable fluid throughsaid temporary opening; d) sealing the temporary opening at the side ofsaid inner container by welding permanent seams; e) enclosing the filledand sealed container in an oxygen barrier forming envelope together withan oxygen absorber; and f) sealing the envelope by means of welding andfinally, sterilizing the container.
 4. A method according to claim 3,characterized by introducing a sheet-formed flexible polymeric materialand attaching to it a sealed port system for fluid communication bymeans of welding, whereupon a bag shaped inner container is formed withthe said port system in its bottom by welding two side seams and a topseam.
 5. A method according to claim 4, wherein one of the side seams isa weak welding capable of providing at least one temporary opening bymeans of the filling equipment.
 6. A method according to claim 5,wherein the temporary openings are sealed by welding a permanent seamsubsequent to the filling of the inner container.
 7. A method accordingto claim 6 characterized by forming at least two chambers by welding atleast one peelable seal seam at a lower temperature and/or pressure thanthe permanent weldings.
 8. A method according to claim 6 characterizedby sterilizing the container by steam.
 9. A method according to claim 5characterized by forming at least two chambers by welding at least onepeelable seal seam at a lower temperature and/or pressure than thepermanent weldings.
 10. A method according to claim 5 characterized bysterilizing the container by steam.
 11. A method according to claim 4,wherein the temporary openings consist of provisional filling portscapable of being sealingly connected to the fluid dispensing means ofthe filling equipment.
 12. A method according to claim 11, wherein saidfilling ports are tubings attached to a side seam in connection to itswelding.
 13. A method according to claim 12, wherein the side of theinner container with the provisional filling ports or filling orificesare cut off subsequent to the filling, whereupon the side of the bag isre-sealed by welding a permanent seam.
 14. A method according to claim13 characterized by forming at least two chambers by welding at leastone peelable seal seam at a lower temperature and/or pressure than thepermanent weldings.
 15. A method according to claim 13 characterized bysterilizing the container by steam.
 16. A method according to claim 11,wherein the side of the inner container with the provisional fillingports or filling orifices are cut off subsequent to the filling,whereupon the side of the bag is re-sealed by welding a permanent seam.17. A method according to claim 16 characterized by forming at least twochambers by welding at least one peelable seal seam at a lowertemperature and/or pressure than the permanent weldings.
 18. A methodaccording to claim 10 characterized by sterilizing the container bysteam.
 19. A method according to claim 11 characterized by forming atleast two chambers by welding at least one peelable seal seam at a lowertemperature and/or pressure than the permanent weldings.
 20. A methodaccording to claim 11 characterized by sterilizing the container bysteam.
 21. A method according to claim 4, wherein at least one fillingorifice is formed in a side seam of the inner container with a shapecorresponding to a filling nozzle of the filling equipment in order toprovide sealing connection during the filling procedure.
 22. A methodaccording to claim 21, wherein the side of the inner container with theprovisional filling ports or filling orifices are cut off subsequent tothe filling, whereupon the side of the bag is re-sealed by welding apermanent seam.
 23. A method according to claim 21 characterized byforming at least two chambers by welding at least one peelable seal seamat a lower temperature and/or pressure than the permanent weldings. 24.A method according to claim 21 characterized by sterilizing thecontainer by steam.
 25. A method according to claim 4 characterized byforming at least two chambers by welding at least one peelable seal seamat a lower temperature and/or pressure than the permanent weldings. 26.A method according to claim 4 characterized by sterilizing the containerby steam.
 27. A method according to claim 3 characterized by forming atleast two chambers by welding at least one peelable seal seam at a lowertemperature and/or pressure than the permanent weldings.
 28. A methodaccording to claim 27 characterized by sterilizing the container bysteam.
 29. A method according to claim 3 characterized by sterilizingthe container by steam.